This Medications Development Center (MDC) for cocaine pharmacotherapy renewal has evaluated over 25 new medications, introduced many new technologies (fMRI, pharma MRI, SPECT, genetics), and facilitated multidisciplinary collaborations among clinical pharmacology, laboratory medicine, neuroimaging, and molecular genetics. We have 78 publications in the past 4 years, covering cocaine genetics (GABA transporter) to vaccines and opiate and nicotine research collaborations with the Chinese National Institute on Drug Dependence. In our continuation we will focus on medication development by modulating norepinephrine (NE) and dopamine (DA) and propose six Specific Aims. 1. To conduct human laboratory cocaine- and methamphetamine (MA)-administration studies with 4 new agents for safety and efficacy: RTI-336 (DA transporter blocker), SY117 (adenosine 2a inhibitor to increase DA activity), and two novel agents, YPK10A and JD-Tic (kappa opiate antagonist) (Proj 1). 2. To conduct two clinical trials of agents modulating NE activity through alpha 1-NE blockade (prazosin and carvedilol) or NE reduction by inhibiting dopamine beta hydroxylase (Proj 2 &3). 3. To test for NE genetic matching of patients to the 3 medications in our two clinical trials. 4. To continue pilot research focused on human genetics for matching new NE and other agents to effective cocaine &MA pharmacotherapies. 5. To attract and train new drug abuse pharmacotherapy investigators through our Center's Core facilities and projects. 6. To disseminate our findings through education and international collaborations. PUBLIC HEALTH RELEVANCE: Cocaine- and MA-dependence are major public health problems in the United States. No FDA-approved treatments for cocaine- or methamphetamine-dependence exist. A greater knowledge of the basic biology of cocaine- and methamphetamine dependence combined with genetic matching for medication response will lead to improved treatments for the disorder. CENTERS CHARACTERISTICS